The treatment of fungal infections remains a major problem in spite of the availability of effective antifungal drugs such as polyenes. The clinical use of these commercial drugs is continuously growing as a result of the increasing incidence of life-threatening fungal infections, particularly in immunocompromised hosts such as cancer patients, patients after transplantation and AIDS patients. However, most of the available polyene antibiotics are toxic and cause side effects that limit their clinical application. The most widely-used polyene antibiotics are amphotericin B (Amph B) and nystatin (Nys)--the drugs of choice for the treatment of mycotic infections caused by a wide range of fungi. The first exists as a parenteral drug in a solubilized form, Fungizone.RTM., and in the more recently developed, less toxic liposomal form, Ambisome.RTM.. However, major technical difficulties associated with the physical stability of liposomes and liposome batch-to-batch reproducibility still need to be overcome in order to allow for a more realistic development of liposomal pharmaceutical intravenous forms of antifungals .sup.(1,2). Although Fungizone.RTM. does not contain liposomes, its therapeutic dose is very close to its maximal tolerated dose (MTD), so that it is usually prescribed only in life-threatening situations. With respect to Nys, the problem of the development of new effective parenteral antifungal drug forms still remains. Although liposomal forms of Nys have been described in the literature .sup.(3), these suffer from problems of drug leakage from liposomes and maintenance of drug chemical integrity, in addition to the problems mentioned above with respect to Amph B. The usage of Nys is therefore currently limited to oral or topical forms, and no parenteral formulations have as yet been developed for this potent drug .sup.(4).
Water soluble, oxidized polysaccharides such as, for example, dextrans are considered to be one of the most attractive drug carrier candidates .sup.(5). Dialdehydedextran (DAD), the main product of the oxidation reaction of periodate with dextran, has been proposed as a stabilizer for enzymes (e.g. U.S. Pat. No. 4,446,316) and drugs, including antibiotics .sup.(6-10). However, no conjugates of polyene antibiotics applicable for parenteral administration have been reported.
GB 978,170 describes a process for the preparation of water-soluble imine derivatives of polyene antibiotics, in which the polysaccharide is oxidized to a polydialdehyde prior to being reacted with the polyene. Among the conjugates described in the above patent are pimaricin-dextran and Nys-corn starch. No amine conjugates are described in the British patent. In experiments carried out by the applicant of the present application, and described in Example 8, it was found that although a Nys-dextran conjugate prepared according to the process described in the above patent is water-soluble, it has very low stability and activity, and is susceptible to drastic degradation of the polymer and inactivation of the conjugated drug. It is believed that this is due to the fact that the oxidized polymer is not purified from excess oxidizing agent prior to conjugation, thus resulting in the polyene undergoing oxidation. This purification is essential for the stability, efficacy and lack of toxicity of the conjugated drug, as will be further described below.
In summary, none of the above studies succeed in documenting a beneficial effect of Nys administration in water-soluble form against systemic fungal infections. Hence, the formation of an IV-injectable, non-toxic system for polyenes in general and Nys in particular remains a problem which limits their use for systemic treatment of serious fungal diseases.